The possible mechanisms of action that I have suggested should be subjected to critical inquiry. Please consult PubMed, the PDSP Ki database, and the referenced literature to decide for yourself if my descriptions are accurate.

Some drugs described as inverse agonists may act as antagonists depending on the cell type and function considered. See Drug-Receptor Interactions by Rob Leurs for an introduction to concepts such as inverse agonism, partial agonism, and antagonism.

See Neurotransmitter.net's list of future treatments for depression, anxiety, sleep disorders, psychosis, and ADHD for information about psychiatric drugs in the FDA's clinical trials process.

Possible Mechanisms of Action:
Amitriptyline inhibits the reuptake of both serotonin and norepinephrine (1). Amitriptyline acts as an antagonist at all subtypes of muscarinic acetylcholine receptors (2). The drug also has antagonist activity at histamine H1 and H2 receptors, serotonin 5-HT2A receptors, and norepinephrine alpha-1 receptors (1). It also binds to histamine H4 receptors (11).

Indications:Treatment of patients with moderate to severe anxiety and/or agitation and depressed mood; patients with depression in whom anxiety and/or agitation are moderate or severe; patients with anxiety and depression associated with chronic physical disease; patients in whom depression and anxiety cannot be clearly differentiated; schizophrenic patients who have associated symptoms of depression

Possible Mechanisms of Action:
Depending on the cell type and function examined, aripiprazole is an agonist, partial agonist, or antagonist at dopamine D2 receptors (13). The drug is a partial agonist at dopamine D3 receptors (13). In addition, it is a partial agonist at serotonin 5-HT1A and 5-HT2A receptors and an inverse agonist at serotonin 5-HT2B receptors (13). Aripiprazole also exhibits significant affinity for serotonin 5-HT7 receptors, alpha-1A-adrenoceptors, and histamine H1 receptors (13).

Possible Mechanisms of Action:
Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) (3). A major metabolite of atomoxetine, 4-hydroxyatomoxetine, is a partial agonist at kappa opioid receptors (4).

Possible Mechanisms of Action:
Bupropion inhibits the norepinephrine and dopamine transporters with low potency (14). A metabolite of bupropion, hydroxybupropion, contributes to the drug's effects as a norepinephrine and dopamine reuptake inhibitor (14). The (2S,3S)- isomer of hydroxybupropion is a much more potent norepinephrine reuptake inhibitor than bupropion. Other bupropion metabolites may also contribute to the drug's effects at the norepinephrine and dopamine transporters (14). Bupropion is a noncompetitive antagonist at nicotinic acetylcholine receptors including the alpha3beta2, alpha4beta2, alpha3beta4, and alpha4beta4 subtypes (14, 15). Bupropion metabolites such as (2S,3S)-hydroxybupropion are also antagonists at nicotinic acetylcholine receptors (14).

Indications:Anxiety disorders or short-term relief of the symptoms of anxiety

Possible Mechanisms of Action:
Buspirone is a partial agonist at serotonin 5-HT1A receptors (17). It also acts as an antagonist at dopamine D2 receptors, but its affinity for these receptors is 16-fold weaker than its affinity for 5-HT1A receptors (18).

Indications:Schizophrenia; nausea and vomiting; relief of restlessness and apprehension before suregery; acute intermittent porphyria; adjunct in the treatment of tetanus; manic episodes associated with bipolar disorder; relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability and poor frustration tolerance

Possible Mechanisms of Action:
Chlorpromazine is an antagonist at dopamine D1 and D2 receptors (21) as well as D3 (22) and D4 receptors (23). The drug may be an inverse agonist at dopamine D2S receptors (133). It also exhibits antagonist activity at serotonin 5-HT2A and 5-HT2C receptors (24). In addition, chlorpromazine is an antagonist at alpha-1A-adrenoceptors (25), alpha-1B-adrenoceptors (25), alpha-2B-adrenoceptors (26), alpha-2C-adrenoceptors (26), and histamine H1 receptors (27). The drug also binds with moderately high affinity to muscarinic M1, M3, M4, and M5 receptors (28). Finally, chlorpromazine binds with high affinity to serotonin 5-HT6 and 5-HT7 receptors (29).

Possible Mechanisms of Action:
Clomipramine inhibits the reuptake of both serotonin and norepinephrine (30). The drug also binds to serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptors, dopamine D2 and D3 receptors, and alpha-1-adrenoceptors (30). Clomipramine acts as an antagonist at muscarinic acetylcholine receptors (31), but the muscarinic receptor subtypes that it affects have not been identified. The drug is also an antagonist at histamine H1 receptors (32). Finally, clomipramine binds to serotonin 5-HT6 receptors (116).

Indications:Panic disorder; alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic seizures, and myoclonic seizures; in patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful

Indications:Treatment-resistant schizophrenia; reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders

Possible Mechanisms of Action: Clozapine is a low affinity inverse agonist at dopamine D2S receptors (106, 133) and a high affinity antagonist at D4 receptors (34). It is also an antagonist at serotonin 5-HT2A (35), 5-HT2B (36), and 5-HT6 receptors (37). Clozapine is an inverse agonist at serotonin 5-HT2C (38) and 5-HT7 receptors (39). The drug is an antagonist at alpha-1A-adrenoceptors and alpha-1B-adrenoceptors (25). Clozapine is also an antagonist at alpha-2A-adrenoceptors and alpha-2C-adrenoceptors (40). Clozapine binds with relatively high affinity to alpha-2B-adrenoceptors (41); it likely acts as an antagonist at these receptors. Depending on cell type and receptor density, clozapine is an antagonist or partial agonist at muscarinic M1, M2, M3, and M4 receptors (42, 43). The drug is also an antagonist at muscarinic M5 receptors (44). Finally, clozapine is an antagonist at histamine H1 receptors (27).

Possible Mechanisms of Action: At plasmalemmal catecholamine transporters, amphetamine indirectly increases the efflux of cytosolic catecholamines
so that they are released into the synaptic cleft (144). The drug causes the release of norepinephrine more potently than it causes the release of dopamine; it is much less effective as a serotonin releasing agent (144) The drug also directly inhibits norepinephrine and dopamine reuptake at higher concentrations (144). Amphetamine- induced activation of protein kinase C (PKC) beta(II) is likely to be responsible for the drug's effect on dopamine efflux (145). Na+ is cotransported with amphetamine as it enters neurons via catecholamine transporters; amphetamine-induced increases in intracellular Na+ may stimulate Na+/Ca2+ antiporters, resulting in an influx of Ca2+ into the cytosol (146). The activity of a Ca2+ dependent enzyme, phospholipase C (PLC), is increased by amphetamine, and PLC may be responsible for the increase in PKC beta(II) activity associated with amphetamine (146). Intracellular dopamine is also required for amphetamine- induced increases in PKC activity (146). Amphetamine increases the activity of phospholipase A2 (PLA2), perhaps by increasing intracellular pH (146). Low PLA2 activity may increase the activation of PKC, while high PLA2 activity may decrease the activation of PKC by amphetamine (146).

Indications:Anxiety disorders or short-term relief of the symptoms of anxiety; symptomatic relief of acute alcohol withdrawal; adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology, spasticity caused by upper motor neuron disorders, athetosis, and stiff-man syndrome; adjunct for convulsive disorders

Possible Mechanisms of Action:
Diazepam is a nonselective benzodiazepine agonist (12). Diazepam is also an agonist at peripheral benzodiazepine receptors (48).

All dosage forms: Monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures; sole or adjunctive therapy in the treatment of simple and complex absence seizures; adjunct for the treatment of patients with multiple seizure types that include absence seizures

Possible Mechanisms of Action:
Divalproex is a histone deacetylase inhibitor (49). The enhancement of gamma-aminobutyric acid (GABA) activity by divalproex is possibly due to the downregulation of GAT-1 and GAT-3 GABA transporter proteins by the drug (50); the cause of this effect is currently unknown. Divalproex also inhibits succinate semialdehyde dehydrogenase (153). At voltage-gated sodium channnels, divalproex shifts the voltage dependence of steady-state inactivation to more hyperpolarized potentials (51); the degree to which this action occurs at therapeutically relevant concentrations in humans is currently not known (52). Finally, divalproex may inhibit T-type calcium channels (53).

Possible Mechanisms of Action:
Doxepin weakly inhibits the reuptake of norepinephrine (54, 130) and serotonin (55, 130). It is a potent antagonist at histamine H1 (56, 57) and H2 receptors (57). Doxepin is also an antagonist at alpha-1-adrenoceptors (56). The drug binds to both serotonin 5-HT2A and 5-HT2C receptors (7). In addition, it is an antagonist at all subtypes of muscarinic acetylcholine receptors (58).

Possible Mechanisms of Action:
Eszopiclone is the S-isomer and biologically active component of zopiclone. Zopiclone potentiates GABA-induced chloride currents in GABA-A receptors that contain the alpha-1 subunit or the combination of the beta2 subunit and the gamma2 subunit (62).

Possible Mechanisms of Action:
Fluphenazine is an inverse agonist at dopamine D1 (64), D2 (27), D3 receptors (65), and D5 receptors (64, 66). Fluphenazine also binds with high affinity to dopamine D4 receptors (9). The drug is an antagonist at serotonin 5-HT2A receptors (24, 27). It has high affinities for serotonin 5-HT6 and 5-HT7 receptors (27, 29). In addition, fluphenazine is an antagonist at histamine H1 receptors (27). The drug also has high affinities for alpha-1A (27), alpha-1B (67), and alpha-2C-adrenoceptors (27).

Indications:Schizophrenia; control of tics and vocal utterances of Tourette's disorder

Possible Mechanisms of Action:
Haloperidol is an inverse agonist at dopamine D1 (64), D2 (72), D3 (65, 73), and D5 receptors (64). The drug is an antagonist at dopamine D4 receptors (74). It binds with relatively low affinity to serotonin 5-HT2A receptors (27). Haloperidol is a partial agonist at alpha-1-adrenoceptors (75). It is also an antagonist at sigma-1 receptors and an agonist at sigma-2 receptors (76).

Indications:For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested; management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus; as a sedative when used as pre-medication and following general anesthesia, hydroxyzine may potentiate meperidine and barbiturates, so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis

Possible Mechanisms of Action:
Hydroxyzine is a histamine H1 receptor antagonist (77). The drug also binds to sigma-1 receptors (78, 79). It may bind to serotonin 5-HT2A receptors as well (80).

Indications:For symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested; management of pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses, and in histamine-mediated pruritus; as a sedative when used as pre-medication and following general anesthesia, hydroxyzine may potentiate meperidine and barbiturates, so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis

Possible Mechanisms of Action:
Hydroxyzine is a histamine H1 receptor antagonist (77). The drug also binds to sigma-1 receptors (78, 79). It may bind to serotonin 5-HT2A receptors as well (80).

Possible Mechanisms of Action:
Imipramine inhibits the reuptake of serotonin and norepinephrine (81). It is an antagonist at histamine H1 and alpha-1-adrenoceptors (82, 130). In addition, the drug is an antagonist at M2 muscarinic acetylcholine receptors (83).

Possible Mechanisms of Action:
Imipramine inhibits the reuptake of serotonin and norepinephrine (81). Imipramine binds to both histamine H1 and alpha-1-adrenoceptors (82). In addition, the drug is an antagonist at M2 muscarinic acetylcholine receptors (83).

Indications:The maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy; adjunctive therapy for partial seizures in adults and pediatric patients (>/= 2 years of age); adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (>/= 2 years of age)

Possible Mechanisms of Action:
Vyvanse is a prodrug of dextroamphetamine. After oral administration, lisdexamfetamine dimesylate is rapidly absorbed from the gastrointestinal tract and converted to dextroamphetamine, which is responsible for the drug's activity.

Chemical Class:
prodrug of the dextro isomer of d,l-amphetamine sulfate

Possible Mechanisms of Action:
Loxapine is an antagonist at dopamine D1 (89), D2 (90), and D3 receptors (91). The drug also binds to D4 and D5 receptors (67). It is an antagonist at serotonin 5-HT2A receptors (92) and an inverse agonist at 5-HT2C receptors (38). In addition, the drug has been found to bind to serotonin 5-HT6 receptors (27). It also binds with low affinity to 5-HT7 receptors (27). Additional binding sites of loxapine include alpha-1A-adrenoceptors, alpha-1B-adrenoceptors, and histamine H1 receptors (67).

Possible Mechanisms of Action:
Maprotiline is a norepinephrine reuptake inhibitor (93). It is also a potent histamine H1 receptor antagonist (94). The drug may act as an antagonist at some muscarinic acetylcholine receptor subtypes (95, 96). Maprotiline is also a weak to moderate affinity antagonist of alpha-1-adrenoceptors (130).

Possible Mechanisms of Action:
Methylphenidate inhibits the reuptake of dopamine and norepinephrine (3). The drug has a higher affinity (~ 10-fold) for dopamine transporters than norepinephrine transporters (3).

Possible Mechanisms of Action:
Methylphenidate inhibits the reuptake of dopamine and norepinephrine (3). The drug has a higher affinity (~ 10-fold) for dopamine transporters than norepinephrine transporters (3).

Possible Mechanisms of Action:
Mirtazapine is an antagonist at serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptors (98). Mirtazapine is also an antagonist at alpha-2-adrenoceptors and histamine H1 receptors (98).

Possible Mechanisms of Action: At plasmalemmal catecholamine transporters, amphetamine indirectly increases the efflux of cytosolic catecholamines so that they are released into the synaptic cleft (144). The drug causes the release of norepinephrine more potently than it causes the release of dopamine; it is much less effective as a serotonin releasing agent (144) The drug also directly inhibits norepinephrine and dopamine reuptake at higher concentrations (144). Amphetamine- induced activation of protein kinase C (PKC) beta(II) is responsible for the drug's effect on dopamine efflux (145). Na+ is cotransported with amphetamine as it enters neurons via catecholamine transporters; amphetamine-induced increases in intracellular Na+ may stimulate Na+/Ca2+ antiporters, resulting in an influx of Ca2+ into the cytosol (146). The activity of a Ca2+ dependent enzyme, phospholipase C (PLC), is increased by amphetamine, and PLC may be responsible for the increase in PKC beta(II) activity associated with amphetamine (146). Intracellular dopamine is also required for amphetamine- induced increases in PKC activity (146). Amphetamine increases the activity of phospholipase A2 (PLA2), perhaps by increasing intracellular pH (146). Low PLA2 activity may increase the activation of PKC, while high PLA2 activity may decrease the activation of PKC by amphetamine (146).

Possible Mechanisms of Action:
Nortriptyline inhibits the reuptake of norepinephrine (100). At serotonin 5-HT2A receptors, nortriptyline is an antagonist (101). The drug is also a low potency antagonist at histamine H1 receptors (102) and some subtypes of muscarinic acetylcholine receptors (103).

Indications:Schizophrenia; acute monotherapy of acute mixed or manic episodes associated with bipolar I disorder; maintenance monotherapy of bipolar patients; combination with lithium or valproate for the short-term treatment of manic episodes associated with bipolar I disorder; Zyprexa intramuscular is indicated for the treatment of agitation associated with schizophrenia and bipolar I mania

Possible Mechanisms of Action:
Olanzapine is a low potency antagonist at dopamine D1 receptors (104, 105). In addition, olanzapine acts as an inverse agonist at dopamine D2 receptors (106). The drug is an antagonist at dopamine D3 (107) and D4 receptors (74). At serotonin 5-HT2A and 5-HT2B receptors, olanzapine is a potent antagonist (105). It also exhibits potent antagonist effects at histamine H1 receptors and alpha-1 adrenoceptors (105). Olanzapine is a low affinity antagonist at M1 and M5 muscarinic acetylcholine receptors (105).

Possible Mechanisms of Action:
Paroxetine is a potent serotonin reuptake inhibitor (45). It also has a moderate affinity for the norepinephrine transporter (45). Paroxetine is a low affinity antagonist at some subtypes of muscarinic acetylcholine receptors (45). In addition, paroxetine is a nitric oxide synthase inhibitor (143).

Possible Mechanisms of Action:
Paroxetine is a potent serotonin reuptake inhibitor (45). It also has a moderate affinity for the norepinephrine transporter (45). Paroxetine is a low affinity antagonist at some subtypes of muscarinic acetylcholine receptors (45). In addition, paroxetine is a nitric oxide synthase inhibitor (143).

Indications:Depressed patients clinically characterized as "atypical," "nonendogenous," or "neurotic." These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features.

Nardil should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions.

Possible Mechanisms of Action:
Phenelzine is an irreversible inhibitor of monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) (111). The drug also inhibits GABA transaminase and alanine transaminase (111).

Indications:Treatment of symptoms of depression in patients who are under close medical supervision. Its activating properties make it particularly suitable for withdrawn and anergic patients

Possible Mechanisms of Action:
Protriptyline is a norepinephrine reuptake inhibitor (115). The drug is an antagonist at some subtypes of muscarinic acetylcholine receptors (117, 130). It is also a low affinity antagonist at histamine H1 receptors (102, 130).

Indications:Schizophrenia; acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex

Possible Mechanisms of Action:
Quetiapine is an antagonist at serotonin 5-HT2A receptors (119). It is also a low potency dopamine D2 receptor inverse agonist (106). Quetiapine is an antagonist at alpha-1A-adrenoceptors (25), alpha-1B-adrenoceptors (25), and alpha-2C-adrenoceptors (40). In addition, the drug is a histamine H1 receptor antagonist (27).

Indications:Schizophrenia; short-term treatment of acute manic or mixed episodes associated with bipolar I disorder; combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder

Possible Mechanisms of Action:
Risperidone is a high potency antagonist at serotonin 5-HT2A receptors (120). The drug also acts as an inverse agonist at dopamine D2 receptors (106) and is an antagonist at D3 and D4 receptors (120). Risperidone is an inverse agonist at serotonin 5-HT1B (121), 5-HT1D (121), and 5-HT2C (38, 122) receptors. It acts as an antagonist at serotonin 5-HT7 (123) receptors. In addition, risperidone is an antagonist at alpha-1A-adrenoceptors (25), alpha-1B-adrenoceptors (25), alpha-2C-adrenoceptors (40), and histamine H1 receptors (27).

Possible Mechanisms of Action:
Selegiline is an irreversible inhibitor of monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) according to the prescribing information for the drug. Selegiline has a greater affinity for MAO-B and is therefore selective for MAO-B at lower dosages (see the prescribing information).

Indications:Management of schizophrenic patients who fail to respond adequately with other antipsychotic drugs

Possible Mechanisms of Action:
Thioridazine binds to dopamine D2, D3, and D4 receptors (67). The drug is an antagonist at serotonin 5-HT2A receptors (24). Thioridazine is also an antagonist at alpha-1A-adrenoceptors and alpha-1B-adrenoceptors (25). In addition, it is an antagonist at M1, M2, M3, M4, and M5 muscarinic acetylcholine receptors (28). Finally, thioridazine is an antagonist at histamine H1 receptors (27).

Possible Mechanisms of Action:
Trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP), are partial agonists at serotonin 5-HT1A receptors (126). At serotonin 5-HT2A and 5-HT2B receptors, trazodone is an antagonist (127). Trazodone and m-CPP are full agonists at serotonin 5-HT2C receptors (128). However, trazodone has a much lower affinity for 5-HT2C receptors than m-CPP (127). The drug is an antagonist at alpha-1-adrenoceptors (129, 130) and a very low affinity antagonist at histamine H1 receptors (130). In addition, m-CPP causes the extracellular release of serotonin through the serotonin transporter (131).

Indications:Schizophrenia; short-term treatment of generalized non-psychotic anxiety (should not be used as the first drug in therapy for most patients)

Possible Mechanisms of Action:
Trifluoperazine is an inverse agonist at dopamine D2 receptors (133). The drug also binds with moderate affinity to dopamine D4 receptors (134). The drug is an antagonist at serotonin 5-HT2A receptors (135) as well as alpha-1A-adrenoceptors and alpha-1B-adrenoceptors (25). Trifluoperazine is a low affinity antagonist at histamine H1 receptors (136). In addition, the drug inhibits interactions between calmodulin and proteins (137).

Possible Mechanisms of Action:
Trimipramine is an antagonist at alpha-1A-adrenoceptors and alpha-1B-adrenoceptors (130, 138) as well as histamine H1 receptors (130). The drug also displays high affinities for serotonin 5-HT2A receptors and dopamine D2 receptors (138).

Indications:Schizophrenia; acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features

Possible Mechanisms of Action: Ziprasidone is an antagonist at serotonin 5-HT2A receptors and dopamine D2 receptors (141). The drug is a partial agonist at serotonin 5-HT1B receptors and an inverse agonist at 5-HT1D receptors (121). Ziprasidone is also an inverse agonist at 5-HT2C receptors (38). The drug is an agonist at 5-HT1A receptors (142) and is known to bind to 5-HT7 receptors (27). Ziprasidone may bind to dopamine D1, D3, and D4 receptors (67). Finally, ziprasidone is a low affinity antagonist at alpha-1-adrenoceptors and histamine H1 receptors (141).